Glioblastoma multiforme (GBM, grade IV astrocytoma) is one of the most common malignant glioma among brain tumors, accounting for 30-40% of primary brain tumors. A significant problem is that as many as 50% of brain tumors are resistant to temozolomide (Temodar), the current standard for chemotherapy for brain tumors. Therefore, there is a need to develop a novel anti-tumor compound for malignant brain tumors; including and especially chemotherapy and radiation resistant brain tumors. We found an analog of thiobarbituric acid (CC-I), and several chemotype moiety compounds (CMC) that had anti-tumor activity for malignant brain tumors by screening against Temodar resistant tumor cells. We have additional evidence that the lead compound CC-1 has topoisomerase inhibition activity, and anti-tumor effect in an in vivo intracranial brain tumor model. In this proposal, we will optimize the anti-tumor effect of CC-I by modification at the N1, N3, and substitution at C5-positions. Therefore, following specific aims are proposed: (1) Identify the two most effective compounds from CC-I and CMC-2 series based on cytotoxicity to glioblastoma cell lines and limited toxicity to normal cell lines, (2) improve the action on topoisomerase II? inhibition, (3) Determine the therapeutic index of the two best compounds identified from aim 1 and CC-I in an in vivo brain tumor model. Because the mechanism of action of these compounds, topoisomerase II? inhibition, is an attractive anti-cancer target, it is possible that the development of these compounds as proposed for malignant brain tumors will be relevant to other tumor types as well. PUBLIC HEALTH RELEVANCE: We have identified a lead compound and chemotype moiety that is cytotoxic to malignant brain tumors including chemotherapy and radiation resistant brain tumors with limited toxicity to normal cells. Based on structure-activity relationship studies, we plan to optimize the anti-tumor effect of our lead compound and will demonstrate in vitro cytotoxicity and determine the therapeutic index of the optimized compounds against the lead compound. The long-term goal of this proposal is to develop a drug that can be positioned for a clinical trial.